1. Field of the Invention
The subject invention relates to an apparatus for fabricating small compacts, and a method for determining if a drug candidate, alone or in a formula mix, is suitable for dry granulation by a roller compactor based on test results generated in part from such small compact. The method is particularly useful when large quantities necessary to run a conventional roller compactor are difficult and/or costly to acquire. The subject invention permits accurate prediction of full-scale production results from relatively small sample sizes of drug candidate.
2. Background of the Related Art
In order for medicinal substances to be compressed into a solid dosage form, such as a tablet, it is necessary that the material possess a number of physical characteristics. These characteristics include the ability to flow freely, cohesiveness, and lubrication.
Free flow of material is necessary to prevent clogging of a conventional compression press. Material to be made into a compact must freely flow from the source of the material to the die. The material must also possess some degree of cohesiveness to keep the compact from crumbling and falling apart on handling. Lastly, the material must have a degree of lubrication in order to minimize friction and to allow for the removal of the compact. With regard to compactions to be used as final dosage forms, they must also possess a suitable degree of hardness, disintegration ability and uniformity.
While certain materials (such as potassium salts, ammonium chloride and methenamine) may be directly compressed into final dosage forms without modifying the physical nature of the material itself, or are therapeutically effective in such low amounts that they may be compressed into a solid dosage form merely by mixing with a diluent possessing suitable compression characteristics, most materials require regimented processing prior to compression. For example, a fine powder may not flow properly into a tablet press or the resulting tablet may not possess the required hardness to maintain integrity during packaging and shipping. Methods of formulation and preparation have been developed to impart desirable characteristics to materials that can not be compressed directly into a final dosage form. Among the methods used to improve the physical characteristics of materials are: forming an admixture with one or more inert substances, communition of the material, and granulation of the material or material formulation.
Addition of one or more inert substances (e.g. excipients) can significantly improve the qualities of a material which is desired to be compressed. Excipients that provide a specific function are well known. In diluting the active with inert substances, it is important that the blend of ingredients for production be homogeneous and provide good powder flow characteristics.
Comminution in its broadest sense is the mechanical process of reducing the size of particles or aggregates and embraces a wide variety of operations including cutting, chopping, grinding, crushing, milling, micronizing and trituration. Materials are often comminuted to improve flow properties and compressibility. Flow properties and compressibility of materials are influenced significantly by particle size or surface area of the particle.
Conversion of powders to granules (a small cohesive mass made up of a plurality of powder particles) frequently offers a number of advantages including improving uniformity of the blend, improving uniformity of particle size, reducing dust hazards, allowing improved product flow, improving uniform bulk density, controlling particle hardness and improving dispersability. Two of the most commonly employed granulation methods are wet-granulation and dry-granulation.
In wet-granulation, a liquid binder solution is combined with a bed of mixed powders to mass the particles together into granules. The damp mass is then screened, dried and milled (as through a comminuting mill or tornado mill) to the desired size. The mass may also be dry screened, lubricated and compressed or extruded through a perforated screen and then dried. In drying, it is often desirable to maintain a residual amount of moisture in the granulation in order to maintain a hydrated state and to reduce static electric charges on the particles. Moisture content of the granulation should be uniform.
Wet granulation suffers from a number of disadvantages. A chief disadvantage is the number of separate steps involved, as well as the time and labor necessary to carry out the procedure. Further, the use of aqueous solvents is limited by the stability of the product to be granulated. Explosion concerns and environmental regulations may limit the use of certain organic solvents.
Dry granulation is used when materials have sufficient inherent binding or cohesive properties to form granules. Dry granulation refers to the process of granulating without the use of liquids. In order for a material to be dry granulated at least one of its constituents, either the active ingredient or a diluent, must have cohesive properties.
Dry granulation may be performed by a process known as xe2x80x9cslugging.xe2x80x9d In xe2x80x9csluggingxe2x80x9d the material to be granulized is first made into a large compressed mass or xe2x80x9cslugxe2x80x9d typically by way of a tablet press using large flat-faced tooling (an example of a linear press is illustrated in U.S. Pat. No. 4,880,373 to Balog et al. which is incorporated by reference herein). A fairly dense slug may be formed by allowing sufficient time for the air to escape from the material to be compacted. Compressed slugs are then comminuted through a desired mesh screen manually or automatically as, for example, by way of a comminuting mill. Formation of granules by xe2x80x9csluggingxe2x80x9d is also known as precompression. When tablets are made from the granulated slugged material, the process is referred to as the xe2x80x9cdouble compression method.xe2x80x9d
Dry granulation may also be performed using a xe2x80x9croller compactor.xe2x80x9d In a roller compactor material particles are consolidated and densified by passing the material between two high-pressure rollers. The densified material from a roller compactor is then reduced to a uniform granule size by milling. The uniform granules may then be mixed with other substances, such as a lubricant, to tablet the material (as, for example, by way of a rotary tableting machine). In addition to pharmaceutical use, roller compaction is used in other industries, such as the food industry, animal feed industry and fertilizer industry.
Dry granulation has several advantages over wet granulation including its usefulness with respect to ingredients that are sensitive to moisture or unable to withstand elevated temperatures during drying, and because it does not use organic solvents which may pose health and environmental hazards. There are also fewer steps involved in dry granulation than wet granulation. Dry granulation by means of roller compaction is an efficient and useful method of granulation capable of handling a large amount of material in a short period of time (dry granulation by xe2x80x9cslugging,xe2x80x9d on the other hand, may be slow, inefficient, and many times requires several attempts at a successful formulation to ensure material flow).
An early understanding of the compaction properties of a candidate drug substance is important. The need for viable dosage forms of candidate drug substances for pharmacological testing purposes, often significantly precedes the ability of a company to synthesize large quantities of the candidate drug. Unfortunately in early-stage pharmaceutical development it is often the case that only small batch sizes of candidate drug substances are available for pharmaceutical and pharmacological characterization. With limited supply of a drug substance available, losses due to the employment of less than efficient formulation techniques may not be easily tolerated.
As stated above, the ability of a material to be dry granulated by a roller compactor offers many advantages. Unfortunately conventional roller compactors require a significant amount of bulk material for operation. Recently Fitzpatrick Company (South Plainfield, N.J.) has introduced a bench top roller compactor for research and development work, the Chilsonator(copyright) IR220 unit. The Chilsonator(copyright) IR220 unit is designed for small scale production. Like other conventional roller compactors, the Chilsonators(copyright) IR220 unit has a horizontal feed screw which carries material to a vertical feed screw, finally depositing material between a drive roll and a driven roll where the material is compacted into a pre-determined shape. Unfortunately the Chilsonator(copyright) IR220 unit still requires at least fifty (50) grams of material for processing, a considerable amount of material in early stage pharmaceutical development.
Given the many different avenues for formulating a drug product, and the many different physiochemical properties displayed by pharmaceutical actives, it is often difficult to determine an efficient methodology for preparing dosage forms containing a newly discovered pharmaceutical active. There is a significant need for methodologies that would allow one to use physical information obtainable from small quantities of pharmaceutical active to arrive at efficient large scale formulation protocols for the drug candidate (without the need for numerous trials and errors with large quantities of pharmaceutical actives using production scale devices).
As direct compaction, and roller compaction using dry granulations, provide numerous advantages in pharmaceutical formulations (not the least of which is the removal of the possibility of reaction of the drug candidate with a solvent as used in wet granulation), it would be advantageous to know using small sample sizes whether the drug candidate could be directly compacted without physical processing (with or without excipients), or compacted after dry granulation by a roller compactor (with or without excipients).
The present invention allows one to extrapolate physiochemical measurements made on bench-scale small sample sizes to efficient production-scale processing. The present invention provides an apparatus and method requiring only small samples ( less than 50 grams) to predict if a substance can be directly compacted or compacted after dry granulated by roller compaction, alone or in combination with excipients. The present method may employ small compacts (comprising less than 50 grams, more preferably less than 30 grams, and yet more preferably less than 10 grams) made by way of a sealed press punch assembly.
In the sealed press assembly of the present invention, upper and lower guide sections house punches that interact in a sealed manner with a die to create compacts. A fill weight adjuster may be used to set the position of one of the punches in its respective guide section. The other punch is dynamically movable in its respective guide section. The press punch assembly of the present invention permits extremely small compacts to be made, and significantly reduces losses of material owing to xe2x80x9cpuffingxe2x80x9d of the compacted material (that is the aerosolization of the material due to expulsion of air during the compaction procedure) due to the sealed relationship of the punches and die.
The present invention provides a method that includes the steps of characterizing the properties of the drug candidate, identifying process parameters suitable to achieve the necessary particle size and density using the dry granulation process, and then translating the laboratory data to a production roller compactor. Information generated from granules derived from compacts made using the press punch assembly of the present invention may, using the teachings set forth herein, be correlated to a production-type roller compactor to produce dry granulated material that has very similar powder/granule characteristics.
In one embodiment of the present invention there is provided a method for determining if a material, or material formulation, is suitable for dry granulation by roller compaction, said method comprising: (a) preparing a plurality of material compacts on a linear press utilizing a plurality of compression forces starting from the minimal force necessary to produce a visibly non-friable compact; (b) milling the plurality of material compacts through a mesh of sufficient size to form granule fractions rather than fine powder fractions; (c) measuring two or more properties of the granule fractions of step (b) selected from the group of properties consisting of: (1) the Carr index, (2) the static angle of repose, and (3) particle size distribution; (d) determining those granule fractions having at least two of the following characteristics: (1) a Carr Index below about 15%; (2) a static angle of repose between about 20xc2x0 and about 40xc2x0, (3) a particle size distribution sufficient for mass flow and homogeneity; (e) adjudging the material or material formulation suitable for dry granulation by roller compaction based on one or more of the granule fractions of step (d) being recompressible into a non-friable compaction with and/or without formula excipients.
In another embodiment of the present invention there is provided a method for setting the compaction pressure of a production scale roller compactor for a particular material/material formulation comprising: (a) preparing a plurality of compacts of the material on a press utilizing a plurality of compression forces starting from the minimal force necessary to produce a visually non-friable compact; (b) milling the plurality of material compacts through a mesh of sufficient size to form granule fractions rather than fine powder fractions; (c) determining the granule fraction having the best flow as characterized by the fraction""s Carr Index and Angle of Repose; (d) setting the compaction pressure per unit area of a production scale roller compactor to a pressure approximately (xc2x120%) the pressure per unit area used to form the compact from which the granule fraction having the best flow was milled.
In yet another embodiment, a second tablet punch is movable with respect to the threaded adjuster. The threaded adjuster defines an adjuster recess. The press punch also includes a tablet ejection plug adapted and configured to couple within the adjuster recess. Upon coupling of the ejection plug into the adjuster recess, the second tablet punch moves with respect to the threaded adjuster.
These and other unique features of the system disclosed herein will become more readily apparent from the following description, the accompanying drawings and the appended claims.